JPH04243879A - New 1,2,3,4,5,6-hexahydroazepino(4,5-b)indoles - Google Patents

Abstract

PURPOSE: To obtain a compound shown by the formula I (A is σ bond, the formula II (R₇ is alkyl); R₁ is H, halogen, OH, alkoxy, alkyl; R₂ is carboxyl, alkoxycarbonyl, carbamoyl, etc., and is H when A is the formula II; R₃ is H, alkyl; R₄, R₅ together form monocyclic or dicyclic 5 to 10-member ring, and are each H, phenyl, alkyl when A is the formula II; R₆ is H, alkyl], e.g. [(3S)-3- methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline]-1-spiro-3'-[2-oxo-2,3- dihydroindole].

CONSTITUTION: The compound is produced from the intermediate of 1,2,3,4,6- hexahydroazepyno [4,5-b] indole shown by the formula VI which is obtained by allowing the substituted tributamine of the formula III to react with the aldehyde of the formula IV in the organic acid of the formula V (R₃ is methyl, ethyl, CF₃).

COPYRIGHT: (C)1992,JPO

Description

Detailed Description of the Invention [0001] [Industrial Application Field] The present invention is novel 1, 2, 3, 4, 5
, 6-hexahydroazepino[4,5-b]indoles and 1,2,3,4-tetrahydro-β-carbolines, methods for producing these compounds, and pharmaceutical compositions containing these compounds. [0002] Prior art: 1, 2, 3, etc. described in the prior art
4,5,6-hexahydroazepino[4,5-b]indole is quite different from the compound claimed by the applicant. That is, none of the preceding compounds has one or two substituents at the 6-position and at the same time hydroxyl, alkoxy or acetoxy at the 5-position. A small number of 5-hydroxy-1,2,3,4,
5,6-hexahydroazepino[4,5,b]indole has been reported to have antitussive properties (French Patent Nos. 1 and 5).
24,830). More generally, 1, 2, 3, 4, 5, 6
-Hexahydroazepino[4,5-b]indoles are very often described as neuroleptics, antidepressants, sedatives, and tranquilizers and as a means of treating cerebrovascular disorders (European patent No. 203,902, European Patent No. 28,381, European Patent No. 64,317
and French Patent No. 1,524,495). [0005] Regarding 1,2,3,4-tetrahydro-β-carboline, many compounds have been produced;
Only two products containing a carboxyl group at the 3-position and a spiran system at the 1-position have been described in the literature, and no pharmacological properties are claimed (Monatsch.
Chem. (1985) 116, pp. 851-5). [0006] Regarding the central nervous system,
More specifically, apart from its good properties as an anxiolytic, antidepressant, and antipsychotic, and in some cases its superior activity in the treatment of cerebrovascular disorders and memory disorders, Certain of the compounds of the invention possess advantageous analgesic, anti-inflammatory, antispasmodic and muscle relaxant properties not possessed by their closest structurally related compounds in the prior art. More specifically, the present invention provides substituted indoles having the formula (I): It relates to addition salts with pharmaceutically acceptable acids or, when R2 is carboxyl, addition salts with pharmaceutically acceptable bases, and when A represents a σ bond, the compounds of the formula (II): 1,2,3,4-tetrahydro-β-carbolines having the formula: When A represents a group having the formula:
I): 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles having the following formula. where R1 is hydrogen, halogen, hydroxyl, straight-chain or branched alkoxy having 1 to 4 carbon atoms, straight-chain or branched alkyl having 1 to 6 carbon atoms (up to 3 halogen, oxo, hydroxyl or 1 optionally substituted with alkoxy having 4 carbon atoms from
R2 is carboxyl, straight-chain or branched alkoxycarbonyl having 1 to 6 carbon atoms (optionally substituted with optionally substituted phenyl), phenylcarbonyl, substituted phenyloxycarbonyl, carbamoyl, nitrogen is 2
represents carbamoyl substituted with straight-chain or branched alkyl having 1 to 6 carbon atoms or cycloalkyl having 4 to 7 carbon atoms, if A is a group having the formula It can also be hydrogen, R3 being hydrogen, straight-chain or branched alkyl having 1 to 6 carbon atoms (up to 3 halogens, oxo, straight-chain or branched alkoxy having 1 to 4 carbon atoms or optionally substituted R4 and R5 are joined together to form a saturated or unsaturated 5- to 12-membered monocyclic or bicyclic ring system; may contain in its ring skeleton from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur, and the ring system may contain up to 3 oxo, straight-chain or branched atoms having from 1 to 6 carbon atoms. alkyl, optionally substituted phenyl, phenylcarbonyl, substituted phenylcarbonyl, optionally substituted phenylalkyl having 7 to 9 carbon atoms, optionally substituted fluorene, and R4 and If R5 forms a bicyclic system, one of the rings may be an optionally substituted aromatic ring, and if A is a group having the formula, R4 and R5 each independently of each other represent hydrogen, optionally substituted phenyl, straight-chain or branched alkyl having 1 to 6 carbon atoms and optionally substituted with up to 2 oxo or optionally substituted phenyl is also possible, provided that A is a σ bond, R1 = R3 = R6 = H, and R2 =
If COOH, R4 and R5 cannot be joined together to form cyclopentyl or cyclohexyl, and if A is the formula R4 and R5 must be other than H. , R6 represents hydrogen or straight-chain or branched alkyl having 1 to 6 carbon atoms and optionally substituted with up to 2 oxo or optionally substituted phenyl, R7 represents hydrogen or a straight line having 1 to 6 carbon atoms and optionally substituted with up to 3 oxo, halogen, alkoxy having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or optionally substituted phenyl. Represents a chain or branched alkyl. The term substituted in the above definitions for the expressions phenyl, phenylalkyl, phenyloxycarbonyl and phenylcarbonyl refers to straight-chain or branched alkyl, the aromatic ring of which has up to three 1 to 6 carbon atoms; It means that it can be substituted with alkoxy, hydroxyl, nitro, trifluoromethyl or halogen having 1 to 4 carbon atoms. The invention also includes processes for obtaining compounds having the general formula (I), and the process for obtaining these compounds depends on the nature of the group A. [0015] A substituted tryptamine having the general formula (IV): [Image Omitted] (wherein R1, R3 and R6 have the same meanings as in the compound of the general formula (I)) is substituted with the general formula (V): [ (wherein R5 and R4 have the same meanings as in the compound of general formula (I)) and these are combined with the aldehyde of the general formula (VI): [wherein R8 is methyl , ethyl, or trifluoromethyl) by heating in an organic acid having the general formula (VII):
has the same meaning as in the case of the compound of general formula (I), R8
has the same meaning as for acid (VI)) 1,2
,3,4,5,6-hexahydroazepino[4,5-b
] indole is obtained and this compound is heated with an alcohol having the general formula R9 OH, where R9 is a branched or other lower alkyl group or an aralkyl group having from 1 to 6 carbon atoms to form the general formula (VIII ): [Chemical Formula 45] (wherein, R1 , R3 , R4 , R5 and R6
has the same meaning as in the case of the compound of general formula (I), R9
1, 2, 3, 4, 5 with the same meaning as above)
, 6-hexahydroazepino[4,5-b]indole or heated in methanol in the presence of 10 equivalents of potassium carbonate to obtain general formula (IX): , R3 , R4 , R5 and R6
1,2,3,4,5,6-hexahydroazepino [
4,5-b] indole, wherein R1 and R6 have the same meanings as in the compound of general formula (I); , R10 is a branched or other lower alkyl or optionally substituted aryl or aralkyl group having from 1 to 6 carbon atoms) with the general formula (XI): R4 and R5 have the same meanings as in the case of the compound of general formula (I)) is reacted with a ketone having the following formula under reflux in toluene or benzene in the presence of p-toluenesulfonic acid under a nitrogen atmosphere. (the water formed during the condensation is removed in a water separator, e.g. a Dean-Stark apparatus), or optionally the reaction is carried out under reflux in methanol or the ketone itself and after purification the general formula (XI
I): embedded image (wherein R1 , R4 , R5 , R6 and R10
has the same meaning as in the compounds of general formulas (I) and (X)), and this compound is converted into a β-carboline having the general formula (XIII): [wherein R11 is a hydrogen atom or an aldehyde having from 1 to 6 carbon atoms and optionally substituted with one or more halogen atoms, alkoxy groups or aryl groups (substituted or unsubstituted); By reacting under reductive amination conditions, general formula (XIV):
] (wherein R1, R10, R11, R4, R5 and R6 have the same meanings as in the compounds of general formulas (XII) and (XIII)) or ): [In the formula, R11 has the same meaning as in the case of the compound of the general formula (XIII)] By reacting with an acid chloride having the following or the corresponding acid anhydride, the compound of the general formula ( XVI): [Chemical formula 53
] (wherein R1, R10, R11, R6, R5 and R4 have the same meanings as in the compound of general formula (XIV)); or, when R10=CH3, In some cases, the general formula (X
VII): to obtain an acid having the formula (wherein R1, R4, R5 and R6 have the same meanings as in the compound of general formula (I)), or to obtain an acid having the formula In the case of general formula (XVIII): embedded image where R12 and R13 each independently represent
by reacting with an amine having the general formula (XIX): embedded image (wherein R1, R4, R5 and R6 have the same meanings as in the compound of general formula (I), and R12 and R13 have the same meanings as in the amide of general formula (XVIII)) An amide having the following formula is obtained. General formulas (VII), (VIII), (IX), (XII), (
Compounds having XIV), XVI), (XVII) and (XIX) form part of the invention and are a special case among the compounds having general formula (I). 1,2,3,4,5 having general formula (I)
, 6-hexahydroazepino[4,5-b]indoles and 1,2,3,4-tetrahydro-β-carbolines, and addition salts thereof with pharmaceutically acceptable inorganic or organic acids; Alternatively, when possible, these addition salts with pharmaceutically acceptable inorganic or organic bases are highly advantageous active ingredients that can be used, for example, as anxiolytics, antidepressants, antipsychotics and analgesics. be. Some of these products are also anticonvulsants, muscle relaxants, anti-inflammatory agents, and are effective in treating cerebrovascular disorders and memory disorders. Compounds of general formula (I) and addition salts with pharmaceutically acceptable inorganic or organic acids, such as hydrochloric acid, methanesulfonic acid, citric acid or maleic acid, or, where possible, pharmaceutically acceptable inorganic or organic acids. Addition salts with inorganic or organic bases such as sodium hydroxide, potassium hydroxide or calcium hydroxide, arginine, ethanolamine or diethanolamine can be used in pharmaceutical preparations, such as tablets, hard gelatin capsules, dragees, etc., according to generally known methods. They can be made into solutions for oral administration, injections, suspensions, emulsions, and suppositories for oral administration. Apart from non-toxic and pharmaceutically acceptable inert excipients such as distilled water, glucose, lactose, starch, talc, vegetable oils, ethylene glycol, etc., these formulations may contain preservatives, stabilizers, wetting agents, It may also contain emulsifiers and the like. The compositions thus obtained are generally presented in the form of metered doses, ranging from 0.1 to 500 mg depending on the condition being treated and the age and weight of the patient.
active ingredients. They can be administered orally, rectally or parenterally, as the case may be, in doses of 0.1 to 500 mg once to several times a day. EXAMPLES The examples described below illustrate the invention and do not limit it in any way. Example 1 [(3S)-3-methoxycarbonyl-1,2,3,4
-tetrahydro-β-carboline]-1-spiro-3'
-[2-oxo-2,3-dihydroindole] 00
31] L(-)-tryptophan methyl ester 2.9
3 g (14.3 mmol), isatin 4.2 g (28.
6 mmol) and 2.7 g of p-toluenesulfonic acid (monohydrate) are heated and dissolved in the minimum amount of methanol that can dissolve the reactants under heating. The reaction medium is refluxed for 48 hours under a nitrogen atmosphere, and then the methanol is distilled off under reduced pressure. The resulting residue was chromatographed on a silica column (eluent: chloroform/methanol).
95/5). The product obtained is then recrystallized from methanol. In this way, 2.55 g (55%) of [
(3S)-3-methoxycarbonyl-1,2,3,4-
Tetrahydro-β-carboline]-1-spiro-3'[
2-oxo-2,3-dihydroindole] is obtained. [0035] Melting point: 253°C Optical rotation: _D (MeOH): -151.6° UV (Me
OH): λmax 215, 225, 245, 28
2 and 285nm IR (KBr): vC=O 1715,1730,1
620cm-1, other absorption bands 3290, 3370cm-
1 1H NMR 300 MHz (CDCl3
) [Chemical formula 57] 13C NMR 75 MHz (C
DCl3) [Chemical formula 58] Example 2 [(3S)-3-methoxycarbonyl-1,2,3,4
-tetrahydro-β-carboline]-1-spirocyclohexane L(-)-tryptophan methyl ester 3 g (14.6 mmol), cyclohexanone 2.86
(29.2 mmol) and 0.28 g of p-toluenesulfonic acid (monohydrate) are dissolved under heat in a sufficient amount of toluene to dissolve the reactants under reflux under a nitrogen atmosphere. The Dean-Stark apparatus allows for the removal of water produced during the reaction. The reaction medium is heated until the starting materials have completely disappeared (
Reflux for about 20 hours) and then remove the toluene by vacuum distillation. The crude product obtained is recrystallized from methanol. This resulted in 3.7 g (89%) of [(3S)-3
-Methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline]-1-spirocyclohexane is obtained. Melting point: 175℃ Optical rotation: αD (MeOH): -
70.9°UV (MeOH): λmax 225,
280 and 285nm 1H NMR 300
MHz (CDCl3) [Chemical formula 59] 13C NMR 75 MHz (CDCl3)
[Chemical formula 60] Example 3 [(3S)-3-carboxy-1,2,3,4-tetrahydro-β-carboline]-1-spirocyclohexane [0042] Saturated barium hydroxide aqueous solution 100 cm3
, 1.5 g of [(3S) in 100 cm3 of dioxane
-3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline]-1-spirocyclohexane solution. The mixture is refluxed for 2 hours and 30 minutes, then cooled and passed through CO2 gas until precipitation of barium carbonate ceases. The precipitate is filtered off and the filtrate is dried. 0.9 g (63%) of [(3S)-3-carboxy-1,2,3,4-tetrahydro-β-carboline]-1-spirocyclohexane is obtained. Melting point: 198-201°C Optical rotation: αD = -69.9° (c = 4.81 gl
-1 MeOH) UV (MeOH): λmax 290, 280 and 220 nm 1H NMR (CDCl3 + CD3 OD) δ:
(ppm) 7.45 d (1H); 7.35 d
(1H); 7.15 t (1H); 7.05 t (
1H); 4.10 dd (1H); 3.35 dd
(1H); 3.22dd (1H); 2.4 to
1.8 (complex and cannot be decomposed) (10H) Example 4 [(3S)-3-methoxycarbonyl-1,2,3,4
-tetrahydro-β-carboline]-1-spirocycloheptane [(3S
)-3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline]-1-spirocycloheptanone is obtained. Melting point: 130-133°C Optical rotation: αD = -55° (c = 6.00 gl-1
UV (MeOH): λmax 288, 280 and 225 nm IR (CHCl3 film): 3400, 1730c
Absorption band at m-1 1H NMR 300 MHz (CDCl3
) [Chemical formula 61] 13C NMR 75 MHz (CDCl3)
[Chemical formula 62] Other signals (CH2) 30.0; 29.6; 2
6.2; 23.1 and 22.4 ppm Example 5 [(3S)-3-(N-propylcarbamoyl)-1,
2,3,4-tetrahydro-β-carboline]-1-spirocyclohexane [(3S)-3-methoxycarbonyl-1,2,3,4
2 g of -tetrahydro-β-carboline]-1-spirocyclohexane and 30 cm@3 of N-propylamine are placed in a sealed tube, and the suspension is then heated at 60 DEG C. for 45 hours. The N-propylamine is removed under reduced pressure and the residue is then purified by chromatography. [(3S)-3-(N-propylcarbamoyl)-1,2,3,4-tetrahydro-β-carboline]-1-spirohexane is obtained in a yield of 50%. Melting point: 225-226°C Optical rotation: αD
=-101.3° (c=5.77 gl-1MeO
H) UV (MeOH): λmax 290, 283 and 225 nm IR (CHCl3 film): 3200 (wide),
Absorption band at 1650cm-1 1H NMR 300
MHz (CDCl3) [Chemical formula 63] 13C NMR 75 MHz (CDCl3)
[Chemical 64] Other signals (CH2) 38.5, 34.3, 2
5.8, 25.4, 22.8, 21.6 and 21.2
ppm Example 6 [(3S)-3-(N-cyclohexylcarbamoyl)
-1,2,3,4-tetrahydro-β-carboline]-
1-spirocyclohexane [0051] In 35 cm3 of cyclohexylamine [(
A suspension of 2 g of 3S)-3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline]-1-spirocyclohexane is heated under reflux for 20 hours under an argon atmosphere. The cyclohexylamine is distilled off and the residue is then purified by chromatography. [(3S)-3-(N-cyclohexylcarbamoyl)-1,2,3,4-tetrahydro-β-carboline]-1-spirocyclohexane was obtained in a yield of 63%. Melting point: 225-230°C Optical rotation: αD = -60.8° (c = 5.75 gl
-1 MeOH) UV (MeOH): λmax 289, 280 and 225 nm IR (KBr) 3290, 1660, 1580 cm-1
1H NMR 300 MHz (CDCl3
) [Chemical formula 65] 13C NMR 75 MHz (CDCl3)
[C66] Other signals (CH2) 38.5, 34.1, 3
3.0, 32.9, 25.8, 25.5, 24.5, 2
1.7 and 21.2 ppm Example 7 [(3S)-3-carbamoyl-1,2,3,4-tetrahydro-β-carboline]-1-spirocyclohexane in a sealed tube [3-methoxycarbonyl- 1, 2, 3, 4-
1 g of tetrahydro-β-carboline]-1-spirocyclohexane is dissolved in 12 cm@3 of methanol, then 3 cm@3 of liquid ammonia are added and the mixture is kept at room temperature for 36 hours. The ammonia gas is removed and the product formed (which gradually crystallizes) is filtered off. This resulted in 0.82 g (82%) of [3-
Carbamoyl-1,2,3,4-tetrahydro-β-carboline]-1-spirocyclohexane is obtained. [0057] Optical rotation: αD = -117.6° (c = 4
．． 02g1-1 DMSO) Melting point (base): 278-279°C; Hydrochloride: 188-1
89℃ UV: λmax 295 220nmIR (KB
r disk): 3500, 3250, 1680, 156
Absorption band at 0 cm-1 1H NMR (base) (CDCl3 +DMSO-
d6 ) δ (ppm) 10.3bs(1H); 7.4d(1H); 7.3d(
1H), 7.05t (1H); 6.95t (1H); 6
．． 8bs (1H); 4.6bs (2H); 3.6m (1
H); 3.15dd (1H); 2.6dd (1H); 2
．． 15dt (1H); 1.9-1.3 (complex and does not decompose) (9H) Example 8 [(3S)-3-methoxycarbonyl-1,2,3,4
-tetrahydro-β-carboline]-1-spiro-4'
-[1-Methylpiperidine] L(-)-tryptophan methyl ester 3.7 g (1
7 mmol), 3.85 g (34 mmol) of redistilled N-methyl-4-piperidone and 0.34 g of p-toluenesulfonic acid (monohydrate) were added to dissolve the reactants under reflux under a nitrogen atmosphere. It is dissolved under heating in a sufficient amount of toluene to remove the water generated during the reaction using a Dean-Stark apparatus. The reaction medium is refluxed until the starting materials disappear (approximately 20 hours) and the toluene is then removed by vacuum distillation. The resulting residue is taken up in chloroform and washed several times with 10% aqueous sodium bicarbonate to remove as much excess N-methyl-4-piperidone as possible. After drying the chloroform solution, the crude product was chromatographed on a silica column (eluent: CHC
13 /CH3 OH with concentration gradient). [0061] As a result, 3.4 g (64%) of [(3S
)-3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline]-1-spiro-4'-[1-
methylpiperidine] is obtained in the form of an amorphous product. Optical rotation: αD (MeOH): -19.5
°UV (MeOH): λmax 220, 280 and 296 nm IR (CHCl3, film) vC=O 1725
and 1740 cm-1 1H NMR 300 MHz (CDCl3
) [Chemical formula 67] 13C NMR 75 MHz (CDCl3)
Example 9 [(3S-3-carboxy-1,2,3,4-tetrahydro-β-carboline]-1-spiro-4'-[1-methylpiperidine] [(3S)- 3-methoxycarbonyl-1,2,3,4
-tetrahydro-β-carboline]-1-spiro-4'
-[1-Methylpiperidine] 1g (31.9 mmol)
20cm3 of distilled water and 2c of 38% potassium hydroxide solution
Add to the mixture with m3. As much dioxane as can be dissolved under heating is added and the reaction medium is kept under reflux for 10 hours under a nitrogen atmosphere. The reaction medium is then concentrated to 2/3 of its volume and 100 mg of Amberlist 77 cationic resin are added. The resin is filtered off and the reaction medium is concentrated under reduced pressure. [0065] As a result, 0.7 g (67%) of [(3S
)-3-carboxy-1,2,3,4-tetrahydro-
β-carboline]-1-spiro-4'-[1-methylpiperidine] is obtained. UV (MeOH): λmax 220
, 280 and 290 nm IR (film) with a wide absorption band at approximately 1700 cm-1 [
Example 10 [(3S)-3-methoxycarbonyl-2-methyl-1
,2,3,4-tetrahydro-β-carboline]-1-
Spiro-4'-[1-methylpiperidine][(3S)-
98 mg (0.31 mmol) of 3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline]-1-spiro-4'-[1-methylpiperidine] and 39 mg of sodium cyanoborohydride at 40% Dissolve in a mixture of 4 cm3 of formaldehyde and 0.5 cm3 of acetic acid. After stirring for 1 hour at room temperature, the reaction medium was reduced to 10%
Pour into aqueous sodium bicarbonate solution and extract with chloroform. The chloroform phase is washed with water, dried over magnesium sulphate and then evaporated to dryness under reduced pressure. [0068] As a result, 95 mg (93%) of [(3S
)-3-methoxycarbonyl-2-methyl-1,2,3
,4-tetrahydro-β-carboline]-1-spiro-
4'-[1-Methylpiperidine] is obtained in the form of a gum. Optical rotation: αD = (MeOH): -8°UV (MeOH
): λmax 225, 280 and 285 nm IR (CHCl3 film) vC=O 1720 and 1735 cm-1 1H NMR 300 MHz (CDCl3
) [Chemical formula 69] 13C NMR 75 MHz (CDCl3)
Example 11 [(3S)-3-carboxy-1,2,3,4-tetrahydro-β-carboline]-1-spiro-4'-piperidinedioxane 70 cm3, water 40 cm3 and 97%
2.5 g of tryptophan in a mixture of 5 cm3 of sulfuric acid
and 1.8 g of 4-piperidone hydrochloride was dissolved,
Heat at reflux for 48 hours under an argon atmosphere. The reaction medium is cooled and the product formed (slowly precipitating) is filtered off. This resulted in 2.3g (62%
) [(3S)-3-carboxy-1,2,3,4-tetrahydro-β-carboline]-1-spiro-4'-piperidine hydrochloride is obtained. UV (MeOH): λmax 295
and 222 nm 1H NMR (CDCl3 + CD3 OD) δ(
ppm) 7.6d (1H); 7.4d (1H); 7.1
5t (1H); 7.05t (1H); 4.2t (1H)
;3.9 multiplet (2-3H);3.5 multiplet (4H);
2.9 multiplet (3-4H) 13C NMR (CD3 OD) δ (ppm) 171
．． 6,137.5,130.0,128.3,123.
5,120.7,119.2,112.4,105.7
,58.3,54.5,43.1,42.0,27.2
,25.9 Example 12 [(3S)-3-methoxycarbonyl-1,2,3,4
-tetrahydro-β-carboline]-1-spiro-4'
-Piperidinebenzene 160cm3 Medium methyltryptophanate 2
．． 18g and 4-piperidone hydrochloride hydrate 1.55g
The suspension is heated to reflux in a Dean-Stark apparatus for 29 hours. The benzene is distilled off, the residue is dissolved in a sufficient amount of methanol, and HCl gas is passed through until saturation. The product which slowly crystallizes out is filtered off. [0074] As a result, 2.15 g (58%) of [(3
S)-3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline]-1-spiro-4'-piperidine is obtained. Melting point: 182-185°C Optical rotation: αD = -46.8° (c = 2.71g1-1
CHCl3/CH3OH, 3:1) UV (MeOH): λmax 295 and 220
nm 1H NMR (DMSO-d6) δ (ppm
) The product is in the dihydrochloride form 11.5s (1H); 9.8s (1H); 9.4s (1
H); 7.5d, J = 7Hz (1H); 7.45d, J
=7Hz (1H); 7.15t J=7Hz (1H)
;7.05t J=7Hz(1H);4.65m(1
H); 3.9d (3H); 3.4m (2H); 3.2-
2.4 (complex and unresolved) (8H)13C NMR
(DMSO-d6)δ(ppm) The product is in dihydrochloride form: Example 13 [5-acetoxy-1,2,3,4,5,6-hexahydroazepino[4,5 -b]indole]-4-spiro-1'-(3'-cyclohexene) 4-bromo-4-formylcyclohexene 1.96 g (
10.37 mmol) is added to a solution of 0.833 g (5.2 mmol) of tryptamine in 50 cm@3 of acetic acid. The reaction medium is then heated to 70° C. for 15 hours under a nitrogen atmosphere. After distilling off the acetic acid under reduced pressure, the residue is taken up in 100 cm 3 of methylene chloride. The organic solution is washed with 100 cm@3 of 10% aqueous sodium carbonate solution, dried over magnesium sulfate and then evaporated to dryness to give 2.52 g of crude product. Chromatography on a silica column (
[5-acetoxy-
1,2,3,4,5,6-hexahydroazepino[4,
1.12 g (70%) of 5-b]indole]-4-spiro-1'-(3'-cyclohexene) as a mixture of two diastereoisomers (the ratio 60:40 is determined by NMR). isolate UV (MeOH): λmax 220
, 280 and 290 nm IR (KBr) vC=O: 1725 cm-1; vC-O
-C: 1245, 1235 cm-1 1H NMR 300 MHz (CD3 OD
) δ (ppm) [0080] 7.55
1H d J = 8Hz C(10)H
7.35
1H d J = 8
Hz C(7)H7.18
1H t J = 8Hz C(8)H
7.1 1H
t J = 8Hz C(9)H
5.85 and 5.71 1H s (
3:2) C(5)-H
5.83-5.73 1H
m C(3') H or C(4
') H 5.66-5.5 1H
m C(4')H or C(3')
H 3.33-3.14 2H
m C(2)-HH'3.14-2.96
2H m C
(1)-HH'2.33-1.63 6H m 2.1 and 2.0 3H s (
3:2) OCOCH3 13C NMR
75 MHz (CD3 OD) δ (ppm) 171.3 (OCOCH3); 135.0 (C6
a); 131.2 (C5a); 127.6 (C 10
a); 126.5 and 126.0 (C3'); 123
．． 3 (C 4'); 122.1 and 121.7 (C
8); 119.4 and 119.2 (C 9);
118.3 and 118.0 (C 10); 113.
3 (C 10b); 111.3 (C 7); 75.
1 and 71.9 (C5); 55.0 (C4)
; 41.9 and 41.8 (C 2); 36.0 and 33.6 (C 2'); 31.7 and 31.4;
26.1; 22.7; 20.7 (OCOCH3) Example 14 [5-Methoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole]- 4-Spiro-
1'-(3'-Cyclohexene) By simply heating at reflux in methanol for 1 hour, [5-
Acetoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole]-4-spiro-1'
-(3'-cyclohexene) can be converted to 5-methoxy compound. UV (MeOH): λmax 220
, 280 and 290nm IR (film) 3380, 3010, 2920, 14
60, 1450, 1090 and 900 cm-1 1H
NMR 300 MHz (CD3 OD) δ(
ppm) [Chemical formula 73] 8.20 and 8.15 1H
bs (3:2) N(6)H
7.52 1
H d J = 8Hz C(10)-H
7.34 1
H d J = 8Hz C(7)-H
7.22-7.06 2
H m C(8)-H+C(9)-H
5.76-5.47 2
H m C(3')-H+ C(4'
)-H 4.18 and 4.00 1H
s(3:2)C(5)-H
3.34 and 3.27 3H
s(3:2) O CH3 3.22-
2.82 4H m
C(1)-HH'+C(2)-HH' 2.75-2.48 1
H m N(3)H
2.34-1.54 6
H m Example 15 [9-methoxy-5-acetoxy-1,2,3,4,5
,6-hexahydroazepino[4,5-b]indole]-4-spiro-1'-(3'-cyclohexene)5-
Starting from methoxytryptamine and using the procedure described in Example 6, [9-methoxy-5-acetoxy-1
,2,3,4,5,6-hexahydroazepino[4,5
-b]indole]-4-spiro-1'-(3'-cyclohexene) is obtained in the form of a diastereoisomeric mixture. UV (MeOH): λmax 220
, 280 and 290 nm IR (film) vC=O: 1710 cm-1; vC-
O-C: 1235, 1215 cm-1 1H NMR 300 MHz (CDCl3
) δ (ppm) [Chemical formula 74] 8.46 1
H bs N(6)H 7.16
1H d C
(7)-H6.94
1H s C(10)-H 6.8
4 1H
dC(8)-H 5.72
1H s C (
5)-H 5.82-5.66
1H m C(3')-H or C(4')H 5.60-5.49 1
H m C(4')-H or C(3'
)-H 3.85 3
H s OCH3 3.29-3.16
2H m C(2)HH' 3.02-2.87 2
H m C (1) HH'2.67-2.52
1H m
N(3)-H2.33-1.64
6H m2.07
3H s CH3C=
Example 16 [5-acetoxy-3-methyl-1,2,3,4,5,
6-hexahydroazepino[4,5-b]indole]
-4-spiro-1'-(3'-cyclohexene)acetic acid 2
N-methyltryptamine 0.2g (1.1
5 mmol) and 0.240 g (1.27 mmol) of 4-bromo-4-formylcyclohexene is heated to 70° C. for 4 days under nitrogen atmosphere. After removing the acetic acid by distillation under reduced pressure, the residue is taken up in 50 cm@3 of methylene chloride and washed with a 10% aqueous sodium carbonate solution. After drying the organic phase over MgSO4, it is filtered and concentrated under reduced pressure. The crude product obtained was subjected to chromatography on silica (
Eluent CH2Cl2/CH3OH, 97%/3%
). Finally, [5-acetoxy-3-methyl-
1,2,3,4,5,6-hexahydroazepino [4,
5-b]indole]-4-spiro-1'-(3'-cyclohexane) is obtained as a mixture of diastereoisomers in a yield of 42%. UV (MeOH): λmax 223
, 285 and 292nm IR (film) 3380, 3000, 2900, 17
10,1450,1360,1330,1230,10
10,950,710 cm-1 1H NMR 300 MHz (CDCl3
) δ (ppm) [Chemical 75] 8.38 and 8.35 1H bs
N(6)-H 7.53
1H d J = 8
Hz C(10)-H 7.27
1H d J = 8Hz C
(7)-H 7.19
1H t J = 8Hz C(8)-
H 7.10 1
H t J = 8Hz C(9)-H 5.
97 and 5.95 1H S (2:3
) C(5)-H 5.79-5.66
1H m
C(3')-H or C(4')-H 5.64-5.47 1H
m C(4')-H or C(3
')-H 3.68-3.54 1H
m C(2)-H
3.46-3.07 3H
m C(2)-H'+C(1)-HH
' 2.90-2.72 1H
m 2.86 and 2.82
3Hs(3:2) N-CH3
2.45-1.80 5H
m Example 17 9-Methoxy-5-acetoxy-4,4-dimethyl-1
,2,3,4,5,6-hexahydroazepino[4,5
-b] 5-methoxytryptamine in 150 cm3 of indole acetic acid 5.3
4g and 2-bromo-2-formylpropane 4.53
The solution of g is heated to 60° C. for 2 hours under nitrogen atmosphere. The acetic acid was distilled off under reduced pressure and the residue was taken up in methylene chloride.
Wash with 10% aqueous sodium carbonate solution. Mg organic phase
Dry over SO4, filter and concentrate under reduced pressure. 9-Methoxy-5-acetoxy-4,4-
Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole is obtained with a yield of 66%. UV (MeOH): λmax 2
15,285 and 300nm IR (film) 3380, 2960, 2940, 28
40,1730(vC=O),1480,1450,1
370,1250 (vC-O-C), 1020,960
cm-1 1H NMR 300 MHz (CDCl3
) δ (ppm) [Chemical formula 76] 8.55 1H
bs N(6)-H 7.16
1H d C
(7)-H 6.94
1H d C(10)-H 6.8
2 1H dd
C(8)-H 3.85
3H s CH3
-O 3.27-3.17
2H m C(1)-H
H'2.96-2.85 2H
m C(2)-HH'2.18
1H bs
N(3)-H 1.20 and 1.2
4 2x3H 2xs -CH3
, -CH3 13C NMR 75 MHz (C
DCl3 ) δ (ppm) 171.1 (C=O), 154.0 (9), 132.6
(5a), 130.0 (6a), 128.3 (10a)
, 113.6 (10b), 112.5 (8), 111.
9 (7), 100.2 (10), 77.6 (5), 55
．． 8 (CH3O), 53.9 (4), 42.6 (2)
,28.8(CH3),27.7(1),23.70
Example 18 5-hydroxy-4,4-dimethyl-1,2,3,4,
5,6-Hexahydroazepino[4,5-b]indole Step 1: 5-acetoxy-4,4-dimethyl-3-trifluoroacetyl-1,2,3,4,5,6-hexahydroaze Pino[4,5-b]indoleacetic acid 150cm
3 A solution of 3.2 g of tryptamine and 3 g of 2-bromo-2-formylpropane was heated to 60°C under a nitrogen atmosphere.
Heat for 5 hours. The acetic acid is removed by distillation under reduced pressure and the residue is taken up in methylene chloride and washed with 10% aqueous sodium carbonate solution. After drying the organic solution, the residue was dissolved in pyridine 10
cm3 and 5 cm3 of trifluoroacetic anhydride. The reaction medium is poured into water, extracted with methylene chloride and then dried. The crude product is recrystallized from acetone. 5
-acetoxy-4,4-dimethyl-3-trifluoroacetyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole is obtained in a yield of 34%. Step 2: 5-hydroxy-4,4-dimethyl-1,2,3,4,5,6-hexahydroazepino [
4,5-b]indole 5-acetoxy-4,4-dimethyl-3-trifluoroacetyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole 2g and carbonic acid 0.7 g of potassium is stirred in 50 cm@3 of methanol under a nitrogen atmosphere at room temperature for 4 hours. After filtration, the product is isolated by extraction with methylene chloride and drying. 5 by dissolving the base in acetone and adding an ethereal solution of hydrochloric acid.
-Hydroxy-4,4-dimethyl-1,2,3,4,5
, 6-hexahydroazepino[4,5-b]indole hydrochloride is obtained. Yield 95% Analysis of base: 0096 UV (MeOH): λmax 220
, 283 and 290nm IR (film) 3380, 2960, 2900, 14
50 cm-1 1H NMR 300 MHz (CDCl3
) δ (ppm) [Chemical formula 77] 8.56 1H
bs N(6)-H
7.45 1H
dC(10)-H7
．． 20 1H d
C(7)-H 7.15
and 7.05 2H t,t C
(9)-H and C(8)-H 4.10 1H
s C(5)-H 3.10-2.70
6H m C(1)-H
H', C(2)-HH', N(3)-H, OH 1.09 3H
s CH31.01
3H s CH3 Example 19 [(3S)-3-methoxycarbonyl-1,2,3,4
Preparation recipe per 1000 tablets containing 50 mg of -tetrahydro-β-carboline]-1-spirocyclohexane [0097] [(3S)-3-methoxycarbonyl
5
0g-1,2,3,4-tetrahydro-β-carboline]-1-spirocyclohexane wheat starch

15g corn starch

15g lactose

50g magnesium stearate

1g silica

1g hydroxypropyl cellulose
2g
Pharmacological study example A of the compound of the present invention Test of anti-inflammatory activity WINTER et al., Proc. Soc. , Exp. Bio
l. Med, 111, 554 (1962) and WIN
EGAR et al., J. Pharmacol. Exp. The
r. The anti-inflammatory potential of the compounds was investigated using a model of acute inflammation induced by subcutaneous injection of carrageenan into the hind paws of rats, following a technique based on the method of 166, 96 (1969). Male Sp with a weight of 200 to 300 g
Raque-Dawley rats were randomly divided into batches of 10 and treated with 0.0% carrageenan in sterile saline.
Locally inject 0.1 ml of 5% suspension into left hind paw 30-6
At 0 min, the test substance is administered intraperitoneally. [0100] The right hind paw was injected with physiological saline to serve as a control. Three hours after carrageenan injection, animals were placed on Na
Animals are deeply anesthetized using rcorem R, and the volumes of both hind paws are measured using a plethysmometer. Results are expressed as percent change in volume v%. [Equation 1] [0103] Anti-inflammatory activity AIA% is defined as follows: [Equation 2] [Table 1] Compound
Dose
AIA% [(3S)-3-methoxycarbonyl 50mg/kg 1
4% -1,2,3,4-tetrahydro-β-carboline]-1-spirocyclohexane [(3S)-3-methoxycarbonyl 25
mg/kg 14% -1, 2, 3,
4-tetrahydro-β-carboline]-1-spiro-4'-[1-methylpiperidine] Example B Testing of analgesic activity The analgesic ability of these products was induced in mice by intraperitoneal injection of acetic acid. Based on counting abdominal twitches,
It was investigated according to the so-called "acetic acid agony" (GAIRIN et al., J. Pharmacol. Exp. Ther. 245
, 955 (1988)). Thirty minutes after the intraperitoneal administration of the test compound to mice randomly divided into batches of 10 mice, 0.3 cm3 of 1% acetic acid is administered intraperitoneally. The number of twitches is counted between 5 and 20 minutes after acetic acid injection. [Table 2] Compounds
Number of twitches/min
(Between 5th and 20th minutes) Control

23±14 [(3S)-
3-methoxycarbonyl-
1±1 1,2,3,4
-tetrahydro-β-carboline]-1-spirocyclohexane, 50 mg/kg The literature compounds that are structurally most closely related to the test compound do not clearly exhibit such analgesic activity. Example C Testing of anxiolytic activity: ``enhanced plus maze'' of the anxiolytic potential of these products
Investigated according to the test. This test uses a reassuring enclosed space (“
The behavior of treated and untreated rats can be examined in situations where they have a choice between an anxiety-producing open space (an "enclosed side street") and an anxiety-producing open space (an "open side street"). This test consists of counting the number of entries into each side path of the maze within a 5 minute period and measuring the time spent on the "open side paths". Rats are randomly divided into batches of 8 rats and given the test compound by intraperitoneal administration 60 minutes before the start of the test. [Table 3] Compounds
Dose Entered Open Sideway Open Sideway

When I spent time in

total number % % between
Contrast
14±2
28%±5% 22%±5% [(3S)-
3-methoxycarbo 50mg 18±2
42%±4% 40%±6% Nil-1
,2,3,4-tetrahy/kg Dro-β-carboline (3S)] IP-1-spirocyclohexane [(3S)-3-methoxycarboline 100mg
18±1 44%±3% 41%±
4% Nyl-1,2,3,4-tetrahy/kg Dro-β-carboline]-1-se IP Pyro-4'-
[1-Methylpiperidine]

Claims (24)

[Claims] Claim 1: Formula (I) [Image Omitted] (wherein A represents a σ bond or a group having the formula, R1 is hydrogen, halogen, hydroxyl, straight-chain or branched alkoxy having 1 to 4 carbon atoms) , represents a straight-chain or branched alkyl having 1 to 6 carbon atoms (optionally substituted with up to 3 halogen, oxo, hydroxyl or alkoxy having 1 to 4 carbon atoms), R2 is carboxyl, 1 to 6 straight-chain or branched alkoxycarbonyl having carbon atoms (optionally substituted with straight-chain phenyl), phenyloxycarbonyl, substituted phenyloxycarbonyl,
Carbamoyl, where A is a radical having the formula , R2 can also be hydrogen and R3 can be hydrogen, straight-chain or branched alkyl having 1 to 6 carbon atoms (up to 3 halogens, oxo, 1
R4 and R5 are bonded together to form a saturated or unsaturated 5- to 12-membered monocyclic ring; or forming a bicyclic ring system, and the ring system may contain from 0 to 3 heteroatoms selected from oxygen, nitrogen and sulfur in its ring backbone, and the ring system may contain up to 3 heteroatoms selected from oxygen, nitrogen and sulfur. oxo, straight-chain or branched alkyl having 1 to 6 carbon atoms, optionally substituted phenyl, phenylcarbonyl, substituted phenylcarbonyl, optionally substituted phenylalkyl having 7 to 9 carbon atoms, optionally substituted may be optionally substituted with fluorene, and if R4 and R5 form a bicyclic system, one of the rings may be an optionally substituted aromatic ring, and if A has the formula R4 and R5 are each independently of one another hydrogen, optionally substituted phenyl, having 1 to 6 carbon atoms and up to 2 oxo or optionally substituted phenyl can also represent an optionally substituted straight-chain or branched alkyl, provided that A is a σ bond, R1 = R3 = R6 = H, and R2 =
If COOH, then R4 and R5 cannot be combined together to form cyclopentyl or cyclohexyl, and if A is a group having the formula (R7 = H or and R6 represents hydrogen or straight-chain or branched alkyl having 1 to 6 carbon atoms and optionally substituted with up to 2 oxo or optionally substituted phenyl; hydrogen or having 1 to 6 carbon atoms and optionally substituted with up to 3 oxo, halogen, alkoxy having 1 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms or optionally substituted phenyl (representing a straight-chain or branched alkyl), its isomers, diastereoisomers, enantiomers, addition salts with pharmaceutically acceptable acids, or when R2 is carboxyl; , addition salts with pharmaceutically acceptable bases (the term substituted in the above definitions for the expressions phenyl, phenylalkyl, phenyloxycarbonyl and phenylcarbonyl means that the aromatic ring has up to three 1 to 6 carbon atoms) straight-chain or branched alkyl, alkoxy having 1 to 4 carbon atoms, hydroxyl, nitro, trifluoromethyl or halogen). 2. A compound according to claim 1, wherein A is selected from substituted indoles of formula (I) representing a σ bond,
1,2,3,4,-tetrahydro-β- having the formula (II), [Image Omitted] (wherein R1, R2, R3, R4, R5 and R6 have the same meanings as in claim 1) A compound corresponding to carboline, its isomer, diastereoisomer, enantiomer, its addition salt with a pharmaceutically acceptable acid, or R
When 2 is carboxyl, an addition salt with a pharmaceutically acceptable base. 3. A compound according to claim 1, wherein A is selected from substituted indoles of formula (I) representing a group having the formula, wherein R1 , R2 , R3 , R4, R5, R
6 and R7 have the same meanings as in claim 1), a compound corresponding to 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles, isomers thereof, Diastereoisomers, enantiomers, addition salts thereof with pharmaceutically acceptable acids, or addition salts thereof with pharmaceutically acceptable bases when R2 is carboxyl. 4. Compounds according to claim 1, wherein R6 is selected from substituted indoles of formula (I), wherein R6 is hydrogen and R3 is either hydrogen or straight-chain or branched alkyl having 1 to 6 carbon atoms. isomers, diastereoisomers, and enantiomers, addition salts thereof with pharmaceutically acceptable acids or, when R2 is carboxyl, with pharmaceutically acceptable bases; 5. [(3S)-3-methoxycarbonyl-1,2 having the formula:
, 3,4-tetrahydro-β-carboline]-1-spiro-3'-[2-oxo-2,3-dihydroindole] or an isomer thereof, or a pharmaceutically acceptable acid. Addition salt with. [Claim 6] [(3S)-3-methoxycarbonyl-1,2 having the formula:
, 3,4-tetrahydro-β-carboline]-1-spirocyclohexane, or its isomer or addition salt with a pharmaceutically acceptable acid. 7. [(3S)-3-methoxycarbonyl-1,2 having the formula:
, 3,4-tetrahydro-β-carboline]-1-spirocycloheptane, or its isomer or addition salt with a pharmaceutically acceptable acid. 8. [(3S)-3-methoxycarbonyl-1,2 having the formula:
, 3,4-tetrahydro-β-carboline]-1-spiro-4'-piperidine, or its isomer or addition salt with a pharmaceutically acceptable acid. 9. [(3S)-3-methoxycarbonyl-1,2 having the formula:
, 3,4-tetrahydro-β-carboline]-1-spiro-4'-[1'-methylpiperidine].
The described compounds, or their isomers or addition salts with pharmaceutically acceptable acids. 10. [(3S)-3-carboxy-1,2,3,4 having the formula:
-tetrahydro-β-carboline]-1-spirocyclohexane, or an isomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or a pharmaceutically acceptable base. 11. [(3S)-3-carboxy-1,2,3,4 having the formula:
-tetrahydro-β-carboline]-1-spiro-4'
- A compound according to claim 1 which is piperidine or an isomer thereof, or an addition salt with a pharmaceutically acceptable acid or a pharmaceutically acceptable base. 12. [(3S)-3-carboxy-1,2,3,4 having the formula:
-tetrahydro-β-carboline]-1-spiro-4'
-[1'-Methylpiperidine], or an isomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or a pharmaceutically acceptable base. 13. [(3S)-3-methoxycarbonyl-2-methyl-1,2,3,4-tetrahydro-β-carboline]-1-spiro-4'-[ having the formula: 1'-methylpiperidine], or its isomer or addition salt with a pharmaceutically acceptable acid. 14. [(3S)-3-carbamoyl-1,2,3, having the formula:
2. The compound according to claim 1, which is 4-tetrahydro-β-carboline]-1-spirocyclohexane, or its isomer or addition salt with a pharmaceutically acceptable acid. 15. [(3S)-3-(N-propylcarbamoyl)-1,2,3,4-tetrahydro-β-carboline] having the formula:
-1-spirocyclohexane, or its isomer or addition salt with a pharmaceutically acceptable acid. 16. [(3S)-3-(N-cyclohexylcarbamoyl)-1,2,3,4-tetrahydro-β-carboline]-1-spirocyclohexane having the formula: 1, or its isomer or addition salt with a pharmaceutically acceptable acid. 17. [5-acetoxy-1,2,3,4,5,6-] having the formula:
hexahydroazepino[4,5-b]indole]-4
-spiro-1'-(3'-cyclohexene), or an isomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid. 18. [5-methoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole]-4- having the formula:
2. A compound according to claim 1 which is spiro-1'-(3'-cyclohexene), or an isomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid. 19. [5-acetoxy-9-methoxy-1,2,3 having the formula:
, 4,5,6-hexahydroazepino[4,5-b]indole]-4-spiro-1'-(3'-cyclohexene), or an isomer thereof, or a pharmaceutical product. Addition salts with acceptable acids. 20. [5-acetoxy-3-methyl-1,2,3,
The compound according to claim 1, which is 4,5,6-hexahydroazepino[4,5-b]indole]-4-spiro-1'-(3'-cyclohexene), or an isomer thereof;
or addition salts with pharmaceutically acceptable acids. 21. 5-acetoxy-9-methoxy-4,4-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b] having the formula: 2. The compound according to claim 1, which is an indole, or an isomer thereof, or an addition salt with a pharmaceutically acceptable acid. 22. 5-hydroxy-4,4-dimethyl-1,2, having the formula:
3,4,5,6-hexahydroazepino[4,5-b]
2. The compound according to claim 1, which is an indole, or an isomer thereof, or an addition salt with a pharmaceutically acceptable acid. 23. A compound according to claim 1, which has a group A
(varies according to the properties of), the general formula (
IV): [Chemical Formula 22] (wherein R1 , R3 and R6 have the same meanings as in the compound of general formula (I)), a substituted tryptamine having the general formula (V): [Chemical Formula 23] (wherein, R5 and R4 have the same meanings as in the compound of general formula (I)), and these are combined with aldehydes having the general formula (VI): is reacted by heating in an organic acid having the general formula (VII):
has the same meaning as in the case of the compound of general formula (I), R8
has the same meaning as for acid (VI)) 1,2
,3,4,5,6-hexahydroazepino[4,5-b
] indole is obtained and this compound is heated with an alcohol having the general formula R9 OH, where R9 is a branched or otherwise lower alkyl group or an aralkyl group having from 1 to 6 carbon atoms to give the general formula ( VIII) : [Chemical formula 26] (wherein, R1 , R3 , R4 , R5 and R6
has the same meaning as in the case of the compound of general formula (I), R9
1, 2, 3, 4, 5 with the same meaning as above)
, 6-hexahydroazepino[4,5-b]indole or heated in methanol in the presence of 10 equivalents of potassium carbonate to obtain the general formula (IX): , R3 , R4 , R5 and R6
1,2,3,4,5,6-hexahydroazepino [
4,5-b] indole, or alternatively, general formula (X): [Image Omitted] wherein R1 and R6 have the same meanings as in the compound of general formula (I) and R10 is A substituted tryptophan having a branched or other lower alkyl or optionally substituted aryl or aralkyl group having from 1 to 6 carbon atoms is substituted with the general formula (XI): embedded image in which R4 and R5 has the same meaning as in the compound of general formula (I)) under reflux in toluene or benzene in the presence of p-toluenesulfonic acid under a nitrogen atmosphere (during the condensation The resulting water is removed in a water separator, e.g. a Dean-Stark apparatus) or optionally reacted under reflux in methanol or the ketone itself and after purification general formula (XII): (In the formula, R1, R4, R5, R6 and R10
has the same meaning as in the compounds of general formulas (I) and (X)), and this compound has the general formula (XIII): [Image Omitted] (wherein R11 is a hydrogen atom or a branched or other lower alkyl group having 1 to 6 carbon atoms, the latter optionally substituted with one or more halogen atoms, a lower alkoxy group having 1 to 4 carbon atoms, or a substituted or unsubstituted aryl group ) under reductive amination conditions to form the general formula (XIV):
2] (wherein R1, R10, R11, R4, R5 and R6 have the same meanings as in the compounds of general formulas (XII) and (XIII)) or to obtain a β-carboline having the general formula ( XV): [Image Omitted] (wherein R11 has the same meaning as in the case of the compound of general formula (XIII)) or the corresponding acid anhydride to form the compound of general formula (XVI) : [Chemical formula 34] (wherein R1, R10, R11, R6, R5 and R4 have the same meanings as in the compound of general formula (XIV)), or
In the case of 10=CH3, by reacting with an aqueous barium hydroxide solution, the general formula (XVII): [Chemical formula 35] or, in the case of R10=CH3, obtain an acid having the general formula (XVIII): where R12 and R13 are each independently of the other,
general formula (XIX): (wherein R1, R4, R5, and R6 have the same meanings as in the compound of general formula (I), and R12 and R13 have the same meanings as in the case of the amide of general formula (XVIII)) The above method (general formula (VII), (VIII), (IX), (
Compounds having XII), (XIV), (XVI), (XVII) and (XIX) form part of the invention and are a special case among the compounds having general formula (I)). 24. A compound according to claim 1 containing as active ingredient, alone or in combination with one or more pharmaceutically acceptable non-toxic inert excipients or vehicles, particularly for the treatment of central nervous system disorders and memory. Pharmaceutical compositions provided in a form suitable for the treatment of disorders, pain, inflammation, severe attacks and convulsions.